Diacylglycerol kinase (dgk) alpha inhibitors and uses thereof

Abstract

Described herein are DGKalpha inhibitors and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for the treatment of a disease or disorder associated with DGKalpha.

What is claimed is: 
     
         1 . A compound of Formula (A), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1a  is halogen, —CN, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; 
         W is N or CR 1b ; 
         each R 1b  is independently hydrogen, halogen, —CN, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; 
         R 2  is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; 
         U is N or CR U ; 
         R U  is hydrogen, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; 
         Ring B is a heterocycloalkyl; 
         each R 3  is independently halogen, —CN, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —SH, —SR a , —S(═O)R a , —S(═O) 2 R, —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; 
         or two R 3  on the same atom are taken together to form an oxo; 
         or two R 3  on the same or different carbons are taken together to form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; 
         m is 0-6; 
         X is N or CR X ; 
         R X  is hydrogen, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; 
         Y is N or CR Y ; 
         R Y  is hydrogen, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; 
         Z is N or CR Z ; 
         R Z  is hydrogen, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; 
         R 5  is hydrogen, halogen, —CN, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, 
       
       
         
           
           
               
               
           
         
       
       cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;
 R 4  is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 4a ; 
 each R 4a  is independently halogen, —CN, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(O)OR b , —OC(═O)NR c R d , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; 
 or two R 4a  on the same atom are taken together to form an oxo; 
 each R a  is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; 
 or two R a  are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; 
 each R b  is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; 
 or two R b  are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; 
 R c  and R d  are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; 
 or R c  and R d  are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and 
 each R is independently halogen, —CN, —OH, —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, or C 3 -C 6 cycloalkyl; 
 or two R on the same atom form an oxo. 
 
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (Aa): 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein R 1a  is —OR a . 
     
     
         4 . The compound of  claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein R 1b  is halogen or —CN. 
     
     
         5 . The compound of any one of  claims 1-4 , or a pharmaceutically acceptable salt thereof, wherein R 2  is hydrogen or C 1 -C 6 alkyl. 
     
     
         6 . The compound of any one of  claims 1-5 , or a pharmaceutically acceptable salt thereof, wherein U is N. 
     
     
         7 . The compound of any one of  claims 1-6 , or a pharmaceutically acceptable salt thereof, wherein Ring B is a 6- to 8-membered heterocycloalkyl. 
     
     
         8 . The compound of any one of  claims 1-7 , or a pharmaceutically acceptable salt thereof, wherein 
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of any one of  claims 1-8 , or a pharmaceutically acceptable salt thereof, wherein m is 0. 
     
     
         10 . The compound of any one of  claims 1-9 , or a pharmaceutically acceptable salt thereof, wherein R X  is hydrogen. 
     
     
         11 . The compound of any one of  claims 1-10 , or a pharmaceutically acceptable salt thereof, wherein R Y  is hydrogen. 
     
     
         12 . The compound of any one of  claims 1-11 , or a pharmaceutically acceptable salt thereof, wherein R Z  is hydrogen. 
     
     
         13 . The compound of any one of  claims 1-12 , or a pharmaceutically acceptable salt thereof, wherein R 5  is 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of any one of  claims 1-13 , or a pharmaceutically acceptable salt thereof, wherein R 4  is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 4a . 
     
     
         15 . The compound of any one of  claims 1-14 , or a pharmaceutically acceptable salt thereof, wherein R 4  is 3- to 6-membered cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R 4a . 
     
     
         16 . The compound of any one of  claims 1-15 , or a pharmaceutically acceptable salt thereof, wherein R 4  is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; each optionally substituted with one or more R 4a . 
     
     
         17 . The compound of any one of  claims 1-16 , or a pharmaceutically acceptable salt thereof, wherein each R 4a  is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, 3- to 6-membered cycloalkyl, or 5- to 6-membered heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. 
     
     
         18 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from a compound found in table 1 or table 2. 
     
     
         19 . A pharmaceutical composition comprising the compound of any one of  claims 1-18 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         20 . A method of inhibiting the activity of at least one of diacylglycerol kinase selected from diacylglycerol kinase alpha (DGKalpha) and diacylglycerol kinase zeta (DGKzeta), in a subject in need thereof, the method comprising administering to the subject the compound of any one of  claims 1-18 , or a pharmaceutically acceptable salt thereof. 
     
     
         21 . A method of inhibiting the activity of diacylglycerol kinase alpha (DGKalpha), in a subject in need thereof, the method comprising administering to the subject the compound of any one of  claims 1-18 , or a pharmaceutically acceptable salt thereof. 
     
     
         22 . A method of modulating the activity of at least one of diacylglycerol kinase selected from diacylglycerol kinase alpha (DGKalpha) and diacylglycerol kinase zeta (DGKzeta), in a subject in need thereof, the method comprising administering to the subject the compound of any one of  claims 1-18 , or a pharmaceutically acceptable salt thereof. 
     
     
         23 . A method of modulating the activity of diacylglycerol kinase alpha (DGKalpha), in a subject in need thereof, the method comprising administering to the subject the compound of any one of  claims 1-18 , or a pharmaceutically acceptable salt thereof. 
     
     
         24 . A method of treating a disease associated with aberrant diacylglycerol kinase signaling, in a subject in need thereof, the method comprising administering to the subject the compound of any one of  claims 1-18 , or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The method of  claim 24 , wherein the diacylglycerol kinase is diacylglycerol kinase alpha. 
     
     
         26 . A method of treating a disease in a subject in need thereof, the method comprising administering to the subject the compound of any one of  claims 1-18 , or a pharmaceutically acceptable salt thereof. 
     
     
         27 . The method of  claim 25 or 26 , wherein the disease is cancer or a viral infection. 
     
     
         28 . The method of any one of  claims 20-27 , wherein the method further comprises administering an additional therapeutic agent. 
     
     
         29 . The method of  claim 28 , wherein the additional therapeutic agent is an anti-cancer agent or an anti-viral agent.